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Title page for ETD etd-03212019-142328


Type of Document Dissertation
Author Banerjee, Amrita
URN etd-03212019-142328
Title Small Intestinal Tuft Cell Specification and Behavior in Homeostasis and Intestinal Inflammatory Disease
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Guoqiang Gu Committee Chair
Christopher S. Williams Committee Member
Christopher V.E. Wright Committee Member
Robert J. Coffey Committee Member
Keywords
  • Intestinal epithelium
  • Crohns disease
  • Tuft cell
  • Mouse models
  • Paneth cell
  • Inflammatory Bowel Disease
Date of Defense 2019-03-13
Availability restrictone
Abstract
Inflammatory Bowel Disease (IBD) and its subtype Crohn’s disease (CD) arise due to a loss of tolerance to environmental antigens in genetically susceptible individuals. Longitudinal analysis of CD incidence has identified an inverse correlation between rates of communicable disease and autoimmune disorders, particularly in countries endemic for helminth infestation. Epithelial tuft cells are responsible for orchestrating the type 2 immune response following helminth colonization and modulation of tuft cell function may prove efficacious in CD treatment. In both human CD samples as well as a mouse model (TNFΔARE/+) of Crohn’s-like ileitis, we observed an inverse correlation between inflammation and tuft cell specification. We applied p-Creode, a novel trajectory mapping algorithm, to single-cell RNA sequencing datasets and demonstrated, contrary to their initial classification, that epithelial tuft cells are specified outside of the canonical secretory lineage. We then developed a novel, genetically-inducible model of tuft cell hyperplasia (AtohKO), where the loss of the master secretory regulator Atonal Homolog 1 drove increased tuft cell numbers in the small intestine. In this model, commensal microbiome-derived succinate, a tricarboxylic acid cycle metabolite, drove tuft cell hyperplasia in the absence of eukaryotic infection. Succinate treatment of TNFΔARE/+ mice increased tuft cell number and suppressed intestinal inflammation. Understanding tuft cell specification and function could enable us to better leverage this rare and elusive cell type to modulate inflammatory symptoms in CD.
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